共查询到20条相似文献,搜索用时 109 毫秒
1.
Jia-Jia Liu Hui Zhang Juan Sun Zhong-Chang Wang Yu-Shun Yang Dong-Dong Li Fei Zhang Hai-Bin Gong Hai-Liang Zhu 《Bioorganic & medicinal chemistry》2012,20(20):6089-6096
A series of novel 4,5-dihydropyrazole derivatives (3a–3t) containing hydroxyphenyl moiety as potential V600E mutant BRAF kinase (BRAFV600E) inhibitors were designed and synthesized. Docking simulation was performed to insert compounds 3d (1-(5-(5-chloro-2-hydroxyphenyl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone) and 3m (1-(3-(4-chlorophenyl)-5-(3,5-dibromo-2-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone) into the crystal structure of BRAFV600E to determine the probable binding model, respectively. Based on the preliminary results, compound 3d and 3m with potent inhibitory activity in tumor growth may be a potential anticancer agent. Results of the bioassays against BRAFV600E, MCF-7 human breast cancer cell line and WM266.4 human melanoma cell line all showed several compounds had potent activities IC50 value in low micromolar range, among them, compound 3d and compound 3m showed strong potent anticancer activity, which were proved by that 3d: IC50 = 1.31 μM for MCF-7 and IC50 = 0.45 μM for WM266.5, IC50 = 0.22 μM for BRAFV600E, 3m: IC50 = 0.97 μM for MCF-7 and IC50 = 0.72 μM for WM266.5, IC50 = 0.46 μM for BRAFV600E, which were comparable with the positive control Erlotinib. 相似文献
2.
Mahmud Tareq Hassan Khan Rasool Khan Yimingjiang Wuxiuer Mohammad Arfan Manzoor Ahmed Ingebrigt Sylte 《Bioorganic & medicinal chemistry》2010,18(12):4317-4327
A combinatorial series of novel quinazolin-4(3H)-ones were synthesised and their structures were established based on spectroscopic data (IR, NMR, EI-MS, and FAB-MS). The compounds were tested for inhibition of the zinc metalloproteinase thermolysin (TLN) utilizing a chemical array-based approach. Some of the compounds were found to inhibit TLN, with IC50 values ranging from 0.0115 μM (compound 3) to 122,637 μM (compound 29). Compound 3 [3-phenyl-2-(trifluoromethyl) quinazolin-4(3H)-one] (IC50 = 0.0115 μM) and compound 35 [3-(isopropylideneamino)-2,2-dimethyl-2,3-dihydroquinazolin-4 (1H)-one] (IC50 = 0.2477 μM) were found to be the most potent inhibitors. 相似文献
3.
《Bioorganic & medicinal chemistry letters》2014,24(19):4638-4642
As a part of our continued efforts to discover new COX inhibitors, a series of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones were synthesized and evaluated for in vitro COX inhibitory potential. Within this series, seven compounds (3a–d, 3h, 3k and 3q) were identified as potential and selective COX-2 inhibitors (COX-2 IC50’s in 1.79–4.35 μM range; COX-2 selectivity index (SI) = 6.8–16.7 range). Compound 3b emerged as most potent (COX-2 IC50 = 1.79 μM; COX-1 IC50 >30 μM) and selective COX-2 inhibitor (SI >16.7). Further, compound 3b displayed superior anti-inflammatory activity (59.86% inhibition of edema at 5 h) in comparison to celecoxib (51.44% inhibition of edema at 5 h) in carrageenan-induced rat paw edema assay. Structure–activity relationship studies suggested that N-phenyl ring substituted with p-CF3 substituent (3b, 3k and 3q) leads to more selective inhibition of COX-2. To corroborate obtained experimental biological data, molecular docking study was carried out which revealed that compound 3b showed stronger binding interaction with COX-2 as compared to COX-1. 相似文献
4.
《Bioorganic & medicinal chemistry》2016,24(2):92-103
A series of (2-benzoylethen-1-ol)-containing benzothiazine derivatives was synthesized, and their herbicidal activities were first evaluated. The bioassay results indicated that some of 3-benzoyl-4-hydroxy-2-methyl-2H-1,2-benzothiazine-1,1-dioxide derivatives displayed good herbicidal activity in greenhouse testing, especially, compound 4w had good pre-emergent herbicidal activities against Brassica campestris, Amaranthus retroflexus and Echinochloa crusgalli even at a dosage of 187.5 g ha−1. More importantly, compound 4w displayed significant inhibitory activity against Arabidopsis thaliana HPPD and was identified as the most potent candidate with IC50 value of 0.48 μM, which is better than the commercial herbicide sulctrione (IC50 = 0.53 μM) and comparable with the commercial herbicide mesotrione (IC50 = 0.25 μM). The structure–activity relationships was studied and provided some useful information for improving herbicidal activity. The present work indicated that (2-benzoylethen-1-ol)-containing 1,2-benzothiazine motif could be a potential lead structure for further development of novel HPPD inhibiting-based herbicides. 相似文献
5.
Amir Assadieskandar Mohsen Amini Marjan Salehi Hamid Sadeghian Maliheh Alimardani Amirhossein Sakhteman Hamid Nadri Abbas Shafiee 《Bioorganic & medicinal chemistry》2012,20(24):7160-7166
A series of 4,5-diaryl-1H-imidazole-2(3H)-thione was synthesized and their inhibitory potency against soybean 15-lipoxygenase and free radical scavenging activities were determined. Compound 11 showed the best IC50 for 15-LOX inhibition (IC50 = 4.7 μM) and free radical scavenging activity (IC50 = 14 μM). Methylation of SH at C2 position of imidazole has dramatically decreased the 15-LOX inhibition and radical scavenging activity as it can be observed in the inactive compound 14 (IC50 >250 μM). Structure activity similarity (SAS) showed that the most important chemical modification in this series was methylation of SH group and Docking studies revealed a proper orientation for SH group towards Fe core of the 15-LOX active site. Therefore it was concluded that iron chelating could be a possible mechanism for enzyme inhibition in this series of compounds. 相似文献
6.
《Bioorganic & medicinal chemistry letters》2014,24(19):4659-4663
A lead compound 1, which inhibits the catalytic activity of PTK6, was selected from a chemical library. Derivatives of compound 1 were synthesized and analyzed for inhibitory activity against PTK6 in vitro and at the cellular level. Selected compounds were analyzed for cytotoxicity in human foreskin fibroblasts using MTT assays and for selectivity towards PTK members in HEK 293 cells. Compounds 20 (in vitro IC50 = 0.12 μM) and 21 (in vitro IC50 = 0.52 μM) showed little cytotoxicity, excellent inhibition of PTK6 in vitro and at the cellular level, and selectivity for PTK6. Compounds 20 and 21 inhibited phosphorylation of specific PTK6 substrates in HEK293 cells. Thus, we have identified novel PTK6 inhibitors that may be used as treatments for PTK6-positive carcinomas, including breast cancer. 相似文献
7.
《Bioorganic & medicinal chemistry》2014,22(15):4285-4292
A series of novel (E)-3-(3,4-dihydroxyphenyl)acrylylpiperazine derivatives had been synthesized and evaluated their biological activities as potential tubulin polymerization inhibitors. Among these compounds, compound 3q exhibited potent antiproliferative activities against three cancer cell lines in vitro, and antitubulin polymerization activity with IC50 of 0.92 μM, which was superior to that of colchicine (IC50 = 1.34 μM). Docking simulation was performed to insert compound 3q into the crystal structure of tubulin at colchicine binding site to determine the probable binding model. These results suggested that compound 3q may be a promising antitubulin agent for the potential treatment of cancer. 相似文献
8.
Takayuki Inoue Masataka Morita Takashi Tojo Akira Nagashima Ayako Moritomo Hiroshi Miyake 《Bioorganic & medicinal chemistry》2013,21(13):3873-3881
Novel thiazole derivatives were synthesized and evaluated as vascular adhesion protein-1 (VAP-1) inhibitors. Although we previously identified a compound (2) with potent VAP-1 inhibitory activity in rats, the human activity was relatively weak. Here, to improve the human VAP-1 inhibitory activity of compound 2, we first evaluated the structure–activity relationships of guanidine bioisosteres as simple small molecules and identified a 1H-benzimidazol-2-amine (5) with potent activity compared to phenylguanidine (1). Based on the structure of compound 5, we synthesized a highly potent VAP-1 inhibitor (37b; human IC50 = 0.019 μM, rat IC50 = 0.0051 μM). Orally administered compound 37b also markedly inhibited ocular permeability in streptozotocin-induced diabetic rats after oral administration, suggesting it is a promising compound for the treatment of diabetic macular edema. 相似文献
9.
《Bioorganic & medicinal chemistry letters》2014,24(22):5207-5211
Structure–activity relationship (SAR) studies around a previously reported antimalarial aminomethylthiazole pyrazole carboxamide 1 are reported. Several analogues were synthesised and profiled for in vitro antiplasmodial activity against the drug-sensitive Plasmodium falciparum malaria parasite strain, NF54. Although all the reported analogues exhibited inferior in vitro antiplasmodial activity (IC50 = 0.125–173 μM) relative to compound 1 (IC50 = 0.0203 μM), one analogue, compound 5a, retained submicromolar activity (IC50 = 0.125 μM). 相似文献
10.
P. Thanigaimalai Ki-Cheul Lee Seong-Cheol Bang Jee-Hyun Lee Cheong-Yong Yun Eunmiri Roh Bang-Yeon Hwang Youngsoo Kim Sang-Hun Jung 《Bioorganic & medicinal chemistry》2010,18(3):1135-1142
The series of imidazoldine-2-thiones 2 and tetrahydropyrimidine-2-thiones 3 were discovered as inhibitor of α-MSH-induced melanin production in melanoma B16 cells. The primary bioassay showed that 1-(4-ethylbenzyl)-tetrahydropyrimidine-2(1H)-thione 3e (>100% inhibition at 10 μM, IC50 = 1.2 μM) and 1-(4-tert-butylbenzyl)-tetrahydropyrimidine-2(1H)-thione 3f (>100% inhibition at 10 μM, IC50 = 0.76 μM) exhibited potent inhibitory effect against α-MSH-induced melanin production. Compounds 3 inhibit the biosynthesis of tyrosinase without affecting its catalytic activity in melanogenesis. 相似文献
11.
《Bioorganic & medicinal chemistry》2016,24(19):4636-4646
New N-4-piperazinyl derivatives of ciprofloxacin 2a–g were prepared and tested for their cytotoxic activity. The primary in vitro one dose anticancer assay experienced promising cytotoxic activity against different cancer cell lines especially non-small cell lung cancer. Independently, compounds 2b, 2d, 2f and 2g showed anticancer activity against human non-small cell lung cancer A549 cells (IC50 = 14.8, 24.8, 23.6 and 20.7 μM, respectively) compared to the parent ciprofloxacin (IC50 >100 μM) and doxorubicin as a positive control (IC50 = 1 μM). The flow cytometric analysis for 2b showed dose dependent G2/M arrest in A549 cells. Also, 2b increased the expression of p53 and p21 and decreased the expression of cyclin B1 and Cdc2 proteins in A549 cells without any effect on the same proteins expression in WI-38 cells. Specific inhibition of p53 by pifithrin-α reversed the G2/M phase arrest induced by the 2b compound, suggesting contribution of p53 to increase. Taken together, 2b induced G2/M phase arrest via p53/p21 dependent pathway. The results indicate that 2b can be used as a lead compound for further development of new derivatives against non-small cell lung cancer. 相似文献
12.
《Bioorganic & medicinal chemistry letters》2014,24(15):3263-3267
Aminochloroquinoline–kojic acid hybrids were synthesized and evaluated for β-haematin inhibition and antiplasmodial activity against drug resistant (K1) and sensitive (3D7) strains of Plasmodium falciparum. Compound 7j was the most potent compound in both strains (IC503D7 = 0.004 μM; IC50K1 = 0.03 μM) and had the best β-haematin inhibition activity (0.07 IC50 equiv vs 1.91 IC50 equiv for chloroquine). One compound 8c was found to be equipotent in both strains (IC50 = 0.04 μM). 相似文献
13.
Stephen Gorsuch Vassilios Bavetsias Martin G. Rowlands G. Wynne Aherne Paul Workman Michael Jarman Edward McDonald 《Bioorganic & medicinal chemistry》2009,17(2):467-474
High-throughput screening led to the identification of isothiazolones 1 and 2 as inhibitors of histone acetyltransferase (HAT) with IC50s of 3 μM and 5 μM, respectively. Analogues of these hit compounds with variations of the N-phenyl group, and with variety of substituents at C-4, C-5 of the thiazolone ring, were prepared and assayed for inhibition of the HAT enzyme PCAF. Potency is modestly favoured when the N-aryl group is electron deficient (4-pyridyl derivative 10 has IC50 = 1.5 μM); alkyl substitution at C-4 has little effect, whilst similar substitution at C-5 causes a significant drop in potency. The ring–fused compound 38 has activity (IC50 = 6.1 μM) to encourage further exploration of this bicyclic structure. The foregoing SAR is consistent with an inhibitory mechanism involving cleavage of the S–N bond of the isothiazolone ring by a catalytically important thiol residue. 相似文献
14.
Ahmed S. Aboraia Sook Wah Yee Mohamed Sayed Gomaa Nikhil Shah Anna C. Robotham Bart Makowski David Prosser Andrea Brancale Glenville Jones Claire Simons 《Bioorganic & medicinal chemistry》2010,18(14):4939-4946
A series of N-(2-(1H-imidazol-1-yl)-2-phenylethyl)arylamides were prepared, using an efficient three- to five-step synthesis, and evaluated for their inhibitory activity against human cytochrome P450C24A1 (CYP24A1) hydroxylase. Inhibition ranged from IC50 0.3–72 μM compared with the standard ketoconazole IC50 0.52 μM, with the styryl derivative (11c) displaying enhanced activity (IC50 = 0.3 μM) compared with the standard, providing a useful preliminary lead for drug development. 相似文献
15.
Laszlo Revesz Achim Schlapbach Reiner Aichholz Janet Dawson Roland Feifel Stuart Hawtin Amanda Littlewood-Evans Guido Koch Markus Kroemer Henrik Möbitz Clemens Scheufler Juraj Velcicky Christine Huppertz 《Bioorganic & medicinal chemistry letters》2010,20(15):4719-4723
Spirocyclopropane- and spiroazetidine-substituted tetracycles 13D–E and 16A are described as orally active MK2 inhibitors. The spiroazetidine derivatives are potent MK2 inhibitors with IC50 <3 nM and inhibit the release of TNFα (IC50<0.3 μM) from hPBMCs and hsp27 phosphorylation in anisomycin stimulated THP-1 cells. The spirocyclopropane analogues are less potent against MK2 (IC50 = 0.05–0.23 μM), less potent in cells (IC50 <1.1 μM), but show good oral absorption. Compound 13E (100 mg/kg po; bid) showed oral activity in rAIA and mCIA, with significant reduction of swelling and histological score. 相似文献
16.
《Bioorganic & medicinal chemistry letters》2014,24(6):1479-1483
A series of novel benzo[b][1,4]oxazin-3(4H)-one derivatives were synthesized as platelet aggregation inhibitors for structure–activity relationships (SAR) analysis. The synthetic pattern, involved Smiles rearrangement for the preparation of benzoxazine, was proven to be more efficient than the conventional methods. Biological evaluation demonstrated that among all the synthesized compounds, compound 9u (IC50 = 9.20 μM) exhibited the most potent inhibition activity compared with aspirin, the positive control (IC50 = 7.07 μM). Molecular docking revealed that these set of compounds could be the GPIIb/IIIa antagonist for that they could be situated in the binding site of GPIIb/IIIa receptor quite well. 相似文献
17.
Yingjie Zhang Jinhong Feng Chunxi Liu Lei Zhang Jie Jiao Hao Fang Li Su Xiaopan Zhang Jian Zhang Minyong Li Binghe Wang Wenfang Xu 《Bioorganic & medicinal chemistry》2010,18(5):1761-1772
Histone deacetylases (HDACs) are enzymes involved in tumor genesis and development. Herein, we report a novel series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as HDACs inhibitors. The preliminary biological screening showed that most of our compounds exhibited potent inhibitory activity against HDACs. Within this series, five compounds, 13a (IC50 = 0.58 ± 0.10 μM), 7d (IC50 = 1.00 ± 0.16 μM), 8l (IC50 = 1.06 ± 0.14 μM), 7i (IC50 = 1.17 ± 0.19 μM) and 7a (IC50 = 1.29 ± 0.15 μM) possessed better HDACs inhibitory activity than Vorinostat (IC50 = 1.48 ± 0.20 μM). So these five compounds could be used as novel lead compounds for further design of HDACs inhibitors. The anti-proliferative activities of a few compounds and the structure–activity relationships are also briefly discussed. 相似文献
18.
Rie Nishikawa-Shimono Yoshinori Sekiguchi Takeshi Koami Madoka Kawamura Daisuke Wakasugi Kazuhito Watanabe Shunichi Wakahara Kayo Kimura Susumu Yamanobe Tetsuo Takayama 《Bioorganic & medicinal chemistry》2013,21(24):7674-7685
In this study, we describe the synthesis and structure–activity relationship (SAR) of a series of isoquinoline chemoattractant receptor–homologous molecule expressed on Th2 cells (CRTH2) antagonists. TASP0376377 (15-20), one of the most potent compounds, showed a potent binding affinity (IC50 = 19 nM) in addition to the excellent functional antagonist activity (IC50 = 13 nM). Moreover, the efficacy of this compound in a chemotaxis assay (IC50 = 23 nM) was in good agreement with its potency as a CRTH2 antagonist. In addition, 15-20 exhibited greater selectivity in binding to CRTH2 than to the DP1 prostanoid receptor (IC50 >1 μM) or the enzymes COX-1 and COX-2 (IC50 >10 μM). 相似文献
19.
6-Chloro-2-Aryl-1H-imidazo[4,5-b]pyridine derivatives 1–26 were synthesized and characterized by various spectroscopic techniques. All these derivatives were evaluated for their antiglycation, antioxidant and β-glucuronidase potential followed their docking studies. In antiglycation assay, compound 2 (IC50 = 240.10 ± 2.50 μM) and 4 (IC50 = 240.30 ± 2.90 μM) was found to be most active compound of this series, while compounds 3 (IC50 = 260.10 ± 2.50 μM), 6 (IC50 = 290.60 ± 3.60 μM), 13 (IC50 = 288.20 ± 3.00 μM) and 26 (IC50 = 292.10 ± 3.20 μM) also showed better activities than the standard rutin (IC50 = 294.50 ± 1.50 μM). In antioxidant assay, compound 1 (IC50 = 69.45 ± 0.25 μM), 2 (IC50 = 58.10 ± 2.50 μM), 3 (IC50 = 74.25 ± 1.10 μM), and 4 (IC50 = 72.50 ± 3.30 μM) showed good activities. In β-glucuronidase activity, compounds 3 (IC50 = 29.25 ± 0.50 μM), compound 1 (IC50 = 30.10 ± 0.60 μM) and compound 4 (IC50 = 46.10 ± 1.10 μM) showed a significant activity as compared to than standard D-Saccharic acid 1,4-lactonec (IC50 = 48.50 ± 1.25 μM) and their interaction with the enzyme was confirm by docking studies. 相似文献
20.
Bhargav A. Patel Ramalingam Krishnan Nikhil Khadtare K.R. Gurukumar Amartya Basu Payal Arora Aaditya Bhatt Maulik R. Patel Dibyendu Dana Sanjai Kumar Neerja Kaushik-Basu Tanaji T. Talele 《Bioorganic & medicinal chemistry》2013,21(11):3262-3271
Hepatitis C virus (HCV) NS5B polymerase is a key target for anti-HCV therapeutics development. Herein, we report the synthesis and in vitro evaluation of anti-NS5B polymerase activity of a molecular hybrid of our previously reported lead compounds 1 (IC50 = 7.7 μM) and 2 (IC50 = 10.6 μM) as represented by hybrid compound 27 (IC50 = 6.7 μM). We have explored the optimal substituents on the terminal phenyl ring of the 3-phenoxybenzylidene moiety in 27, by generating a set of six analogs. This resulted in the identification of compound 34 with an IC50 of 2.6 μM. To probe the role of stereochemistry towards the observed biological activity, we synthesized and evaluated the d-isomers 41 (IC50 = 19.3 μM) and 45 (IC50 = 5.4 μM) as enantiomers of the l-isomers 27 and 34, respectively. The binding site of compounds 32 and 34 was mapped to palm pocket-I (PP-I) of NS5B. The docking models of 34 and 45 within the PP-I of NS5B were investigated to envisage the molecular mechanism of inhibition. 相似文献